ABSTRACT/SUMMARY Candidate: I am a Pulmonary/Critical Care physician with a long-standing commitment to becoming a physician-scientist. My short-term goal is to develop the skills necessary to study alcohol's effect on innate immunity, epigenetic changes caused by alcohol and in vivo models of alcohol consumption. These skills will provide me with the tools necessary to prepare a competitive R-01 at the end of my training period. My long- term career goal is to become a leader in the field of alcohol research by advancing the understanding of alcohol-induced changes to the innate immunity of the lung. Research Plan: We will structure my training around the goal of determining the mechanisms through which alcohol modulates the expression of Toll-like receptor 2 (TLR2) in the airway epithelium. TLR2 is an important modulator of airway inflammation induced by gram-positive bacteria. This inflammatory response contributes to airway diseases such as bronchitis and chronic obstructive pulmonary disease. We have shown that brief alcohol exposure leads to an increase in the expression of TLR2, while prolonged expression leads to a decrease of TLR2. We will determine the mechanism of this biphasic effect of alcohol by addressing the following specific aims: 1) Determine the mechanism of alcohol's modulation of RhoA activity, and how this regulates TLR2 expression in the airway epithelium. 2) Characterize the alcohol-induced epigenetic changes that lead to transcriptional changes in TLR2. 3) Determine the functional significance of alcohol's biphasic modulation of TLR2 in vivo. I will require additional training to be able to complete these aims. Specifically, I will take courses in epigenetics, cell signaling and statistics. I will receive hands on training in techniques related to epigenetic studies. I will attend alcohol-related journal clubs, conferences and lab meetings. I will also attend and present my data at national and international meetings. Environment: My chosen Mentor, Dr. Todd Wyatt, is a recognized expert in cyclic nucleotide signaling and funded alcohol lung researcher. In addition, the University of Nebraska Medical Center has numerous NIAAA funded researchers who will provide intensive mentoring for me during my training period. My department has committed 75% protected time for research, a technician, laboratory and office space, start-up funds, and equipment. Public health relevance: Our long-term goal is to understand why alcoholics have more severe airway disease of the lung. A better understanding of how alcohol influences inflammatory processes in the lung will lead to more targeted therapy of airway disease in alcoholics and result in decreased morbidity and mortality.